Who decides what’s an analog of a controlled substance?

“We’re like a naughty Holland & Barrett”: John Clarke, a pharmacology graduate, and Jo Hall have been selling legal drugs (in the UK) since 2006. Photograph: Suki Dhanda/UK Observer magazine

In this quiet week of reflection around the blogosphere, it makes sense that I should put up one last post on the topic that has brought us the most attention this year: synthetic cannabimimetics that have been sold in herbal incense blends such as K2 Spice. While marketed as “not for human consumption,” these products exemplify the growing legal highs industry (Coffeesh0p.com, a UK company run by John & Jo, pictured right, is a well-known example.).

Let’s take a moment to re-hash (I can’t help myself) these marijuana mimics before getting to the question posed in the title.

This series of compounds first synthesized by the laboratory of John W. Huffman at Clemson were originally investigated to establish structure-activity relationships for non-cannabinoid agonists at CB1 and CB2 endocannabinoid receptors. (See this post for more background from us and others about these compounds.) That is, Huffman and his collaborator, the late Billy Martin, were testing what structures similar to or different from the naturally-occurring compounds in marijuana could still allow high potency binding and modulation of these receptors.

Endocannabinoid inverse agonists have been explored by several pharmaceutical companies as anti-obesity drugs via appetite reduction (the opposite effect of marijuana). Unfortunately, many of these compounds have failed – rimonabant (Acomplia), most notably – due to increased risk of depression and suicide. Carmen Drahl had an extensive 2009 C&EN cover story on these compounds and other anti-obesity strategies.

But the Huffman compounds and others in herbal incense products are endocannabinoid agonists that produce sensory experiences similar to marijuana, albeit in a dose-dependent manner. As with any drug, too much can produce adverse reactions. All year, US municipalities and 15 states have criminalized the sale, possession, and/or use of products containing these compounds as hospitals and poison control centers began tallying cases of users seeking medical attention for extreme anxiety, hallucinations, and even seizures. Although a few deaths were at first associated with Spice products, other drugs were ultimately implicated in the one Indiana case that received the greatest publicity.

This blog is not a formal reporting entity but we’ve accumulated a couple hundred comments across ourposts in the variousiterations of Terra Sigillata and the new Take As Directed blogs that existed during 2010. Those comments are about equally split as to the real health risks with these psychoactive compounds. Some readers were of the mind that inexperienced adolescent users were simply using too much of the products and experiencing panic attacks. Here, we’re talking about medically-classified panic attacks, described here at WebMD, where individuals feel intense terror together with autonomic symptoms that further reinforce the fear, even to evoking a sense of impending death. Others – particularly those reporting long-term marijuana use – contended that these products are very different from marijuana and are easier to overdose. No surprise that many in this group of commenters suggested the work-around of simply legalizing marijuana and the K2 Spice problem would go away.

Last week, we discussed elsewhere the anticipation of a final rule from the US Department of Justice’s Drug Enforcement Agency that proposes to temporarily ban five compounds – including three of Huffman’s – that have been detected in herbal incense blends and also sold in allegedly pure forms online.

The United States Drug Enforcement Administration (DEA) is using its emergency scheduling authority to temporarily control five chemicals (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) used to make “fake pot” products. Except as authorized by law, this action will make possessing and selling these chemicals or the products that contain them illegal in the U.S. for at least one year while the DEA and the United States Department of Health and Human Services (DHHS) further study whether these chemicals and products should be permanently controlled.

Assignment of these five compounds to the DEA Schedule I class of compounds for a year has caused legal high manufacturers to to clear the shelves of the current products – described by one marketer as, “the best Christmas gift that the good old USofA could have given me” - and create products containing other compounds not explicitly named in the DEA emergency scheduling announcement.

However, the DEA reserves the right to similarly regulate any analogs of Schedule I drugs that are intended for human consumption. In fact, one of the finest substance abuse blogger-scientists out there, Drugmonkey, mused back in February whether sale/possession of even the now outlawed compounds could have been prosecuted back then because the Controlled Substances Act contains a provision to regulate structurally or pharmacologically similar compounds:

They are structurally or pharmacologically similar to Schedule I or II controlled substances and have no legitimate medical use. A substance which meets the definition of a controlled substance analogue and is intended for human consumption is treated under the CSA as if it were a controlled substance in Schedule I.

I understand that many legal high companies contend they are in compliance with the law by indicating that their products are not intended for human consumption. This is akin to dietary supplement manufacturers being required by FDA to indicate on their labels, “This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.” And, indeed, other JWH compounds are pharmacologically similar to those now explicitly banned.

But how does the DEA decide what an analog(ue) is?

(Aside: I know, I know – real chemists use the term, “analog,” and the use of “analogue” in the federal act was a point of much ridicule. Interestingly, a search of PubMed this morning for “analogue” heretically brought in more returns than for “analog” – 67,047 to 56,978. Of course, most of the misuse of the term is due to us biologists. A search of C&EN back to 1998 properly brought back 956 results using “analog” with only 9 for “analogue,” with most of the latter coming from article citing titles with the improper use in peer-reviewed journal articles.)

Analogs or not?

In the case of JWH-018, -073, and -200, all compounds are all C5-substituted naphthoylindoles. One commenter indicated to us that JWH-250 is now being used in some of the new products – does this skirt the analog provision because the naphthalene is replaced by a 2′-methoxyphenyl group?

Indeed, some of the long-term health concerns with the naphthoylindoles is that cytochrome P450-mediated epoxidation of the naphthalene could create a carcinogen. This metabolic oxidation product would not occur in JWH-250.

The Count Your Culture blog expands upon these compounds and their pharmacological properties with two excellent posts (1, 2) earlier this month written from the standpoint of the legal highs chemist. We can have a whole separate discussion on another day as to the ethics and values of synthesizing sort-of-legal psychoactive compounds for sale to folks of a consenting age or younger. But I have always been fascinated intellectually by the Whack-A-Mole agility of clandestine chemists in response to DEA actions. I’m also equally intrigued as to why the DEA chose to select only five compounds in their emergency action.

In this regard, it’s only appropriate to close with quotes from the 77-year-old Dr. Huffman himself:

JWH-018 was “nothing special”, Dr Huffman remembered, “but it was one of the more potent compounds we made, and it was quite easy to make from commercially available materials. Probably the reason it has now caught on.”

[. . .]

“My biggest surprise was that this all hadn’t happened sooner,” he told me. “All it needed was somebody with a reasonable understanding of science to see the papers we had published and think, ‘Aha!’”

And, finally:

“I’ve lived around the world a long time,” said Dr Huffman. “I’ve come to the conclusion that if an enterprising person wants to find a new way to get high, they’re going to do it.”

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2 Comments

wishdoctor

11 April 2013

Congress made a very glaring tyographical error in the 1986 Act that causes the courts to apply their own editorial correction that goees beyond the plain language.

I find it puzzling that very few people notice the gramamatical ambiguity off the Act in its omission of the word “and” after (i) and the widespread assumption that the “and” after (ii) applies to the conjunction of (i) and (ii) which are linked with a “or.”

“[a] controlled substance analogue shall, to the extent intended for human consumption, be treated . . .as a controlled substance in Schedule I.” The term “controlled substance analogue” is defined as a substance:

(i) the chemical structure of which is substantially similar to the chemical structure of a controlled substance in schedule I or II;

(ii) which has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II; or

(iii) with respect to a particular person, which such person represents or intends to have a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II.
——

(32)
(A)Except as provided in subparagraph (C), the term “controlled substance analogue” means a substance—
(i)the chemical structure of which is substantially similar to the chemical structure of a controlled substance in schedule I or II;

(ii)which has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II; or

(iii)with respect to a particular person, which such person represents or intends to have a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II.

(B)The designation of gamma butyrolactone or any other chemical as a listed chemical pursuant to paragraph (34) or (35) does not preclude a finding pursuant to subparagraph (A) of this paragraph that the chemical is a controlled substance analogue.

(C)Such term does not include—
(i)a controlled substance;

(ii)any substance for which there is an approved new drug application;

(iii)with respect to a particular person any substance, if an exemption is in effect for investigational use, for that person, under section 355 of this title to the extent conduct with respect to such substance is pursuant to such exemption; or

(iv)any substance to the extent not intended for human consumption before such an exemption takes effect with respect to that substance.

wishdoctor

11 April 2013

In brief, the Act defines Analogues as:
i ;
ii; or
iii.

Because there are three conditions linked only by one “or” it’s logical to infer a “or” after i, which would be so broad a definition as to make it absurd and without needed rational basis and thus unconstitutional for vagueness and lack of rational basis.

Courts have redefined the language by interpreting it as [i AND ii] OR iii. But does that make any sense, really?

And you say it’s up to the DEA to interpret it and declare specific substances as analogues but the sthat finding would rest on the *intent* of the marketer, not any inherent quality of the substance.

Any federal judge could send that typographical error back to Congress, but it hasn’t happened.

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